Alzheimer's disease (AD) is a major concern as the population ages, with no truly effective treatments available. One of the hallmarks of the disease is the deposition of insoluble plaques composed of a peptide derived from Amyloid Precursor Protein (APP). Message has established a drug discovery program focused on regulating protein expression by altering the interaction of an RNA binding protein with its target RNA. The overall goal of this project is to use this technology to develop drugs that decrease levels of APP. The current proposal seeks to (1) identify all the necessary components involved in these interactions; (2) screen for compounds that alter the interactions; (3) analyze effects of the compounds in cell culture; and (4) determine the in vivo efficacy in animal models of AD. Successful completion of this work will result in preclinical drug candidates and ultimately in a novel treatment targeting AD progression. To date, we have demonstrated that Message is regulated at the post-transcriptional level and that phenserine can block translation of the APP mRNA in a specific fashion. Analogs are currently being tested for more potent molecules and a high throughput screen will be developed once the regulatory regions are better understood. PROPOSED COMMERCIAL APPLICATION: Successful completion of this project will provide compounds for preclinical development as AD therapeutics. All current treatments for AD treat the symptoms (cognition) whereas this strategy would target a key factor believed to play a role in causing the disease. In addition, validation of post-transcriptional drug targeting would have broad implications for the treatment of other diseases.